Tricyclic compounds

ABSTRACT

Tricyclic compounds of the formula :   WHEREIN: A is -(CH2)m-, -CH CH- , -(CH2)p-O- , -(CH2)p-S- , -(CH2)pSO2-, -(CH2)p-NR1 or -SO2-NR2- in which m is 1, 2 or 3, p is 1 or 2, R1 is hydrogen or lower alkyl and R2 is lower alkyl ; X and Y are hydrogen or halogen ; R and R&#39;&#39; are hydrogen or lower alkyl, and N IS AN INTEGER OF FROM 1 TO 12 INCLUSIVE. These compounds possess psychostimulant, antidepressive, analgesic, antitussive, antihistaminic and gastric antisecretory properties.

United States Patent 11 1 Malen et al.

[ Sept. 11, 1973 1 TRICYCLIC COMPOUNDS [75] Inventors: Charles Malen,Fresnes; Bernard Danree, St. Germain en Laye; Jean-Claude Poignant,Wissous, all of France [73] Assignees: Societe en nom collectif ScienceUnion Et Cie; Societe Francaise De Recherche Medicale, Suresnes, France22 Filed: Mar. 13, 1970 21 Appl. No.: 19,503

[56] References Cited UNITED STATES PATENTS 3,535,315 10/1970 Winter eta1. 260/518 R Primary ExaminerLorraine A. Weinberger AssistantExaminerL. Arnold Thaxton AttorneyGordon W. Hueschen [57] ABSTRACTTricyclic compounds of the formula or 3, p is 1 or 2, R is hydrogen orlower alkyl and R is lower alkyl X and Y are hydrogen or halogen R and Rare hydrogen or lower alkyl, and

n is an integer of from 1 to l2 inclusive.

ITEE "E6H1F6i1nds "passes psychostimulant, lamidepressive, analgesic,antitussive, antihistaminic and gastric antisecretory properties.

5 Claims, No Drawings 3,75s,52s s TRICYCLIC COMPOUNDS The presentinvention provides tricyclic compounds of the general formula I whereinA is a bridge selected from the following radicals m is an integer offrom 1 to 3 inclusive p is an integer selected from 1 and 2 R isselected from the group consisting of a hydrogen atom and a lower alkylradical containing from one to five carbon atoms inclusive, and

R is a lower alkyl radical containing from one to five carbon atomsinclusive X and Y are the same or different and each is selected fromthe group consisting of a hydrogen atom and a halogen atom selected fromfluorine, chlorine and bromine atoms R and R are the same or differentand each is selected from the group consisting of a hydrogen atom and alower alkyl radical containing from one to five carbon atoms inclusivein a straight or branched chain and n is an integer of from 1 to 12inclusive.

The compounds of the general formula 1 in which R represents a hydrogenatom are amphoteric compounds which yield metal salts with bases of thealkali or alkaline earth metals, such, for example, as sodium, potassiumor calcium hydroxide, carbonate and bicarbonate, and salts withinorganic or organic acids, such, for example, as hydrochloric,hydrob'romic, sulfuric, phosphoric, acetic, propionic, maleic, fumaric,methane sulfonic, tartaric, citric, oxalic and benzoic acids. Thecompounds of general formula I in which R represents an alkyl radicalare basic compounds which yield salts with inorganic or organic acidsmentioned above.

\4 l 'lul in which A, X and Y have the meanings given above 65 and Halrepresents a chlorine or bromine atom, with an aliphatic w-amino-esterof general formula III:

R NH (CH COOR' [II in which R and n have the values given above and Rrepresents a lower alkyl radical containing one to five carbon atoms, soas to yield the compounds of the general formula 1 in which R is a loweralkyl radical, and then saponifying the ester so obtained to yield acompound of the general formula I in which R is a hydro gen atom.

The condensation is carried out in a suitable organic solvent, forexample, nitromethane, acetonitrile or dimethylformamide, in thepresence of an acceptor of the hydracid formed during the reaction. Thisacceptor may be an excess of the w-amino-ester (III), a tertiary Mamine, a pyridine base, or an alkali or alkaline earth carbonate orbicarbonate. The reaction is generally slightly exothermic and takesplace at a temperature preferably within the range of from 20 to 100C.

The saponification of the resulting ester is carried out either in analkaline aqueous alcoholic medium or in a strongly acid aqueousalcoholic medium.

The halogenated starting compounds I] have been prepared by methodswhich are in themselves known starting from the correspondinghydroxylated compounds, which are either treated with dry hydrochloricscid or with thionyl chloride. These hydroxylated compounds arethemselves prepared from the corresponding ketones, the majority ofwhich are known compounds.

The physical constants of the new starting materials, whether they beketones, alcohols or halides, are given in the Examples which follow.

The undermentioned Examples illustrate the inven tion. The meltingpoints are, unless otherwise stated, determined on a Kofler block. Theyare in fact decomposition points, the determination of which is ratherimprecise.

EXAMPLE 1 7-[dibenzo (a,d) cycloheptadien-S-yl] aminoheptanoic acidhydrochloride CHy-CH:

6,5 g of 5-chloro-l0, ll-dihydro-SH-dibenzo (a,d) cycloheptene in 60 mlof nitromethane and 10,8 g of ethyl 7-aminoheptanoate in 12 ml ofnitromethane were mixed at ambient temperature. The reaction wasslightly. exothermic. The reaction mixture was left to stand overnightand the solvent was evaporated in vacuo. The residue was taken up innormal hydrochloric acid and the resulting precipitate was filtered off.

10.5 g of crude ethyl 7-[dibenzo (a,d) cycloheptadiene-S-yl]aminoheptanoate hydrochloride were obtained, of which a samplerecrystallised from benzene gave a pure product melting instantaneouslyat 166 to 168C.

The hydrochloride of the crude ester obtained above was added to 25 mlof 2N hydrochloric acid. The whole was kept under reflux for 2 hours.The material dissolved and a new hydrochloride then reprecipitated.After cooling, the hydrochloride of the crude acid was filtered off,washed with iced water and then recrystallised from distilled water. 5.7g of 7-[dibenzo (a,d) cycloheptadien-S-yl] aminoheptanoic acidhydrochloride were obtained, melting instantaneously at 226 to 230C.

EXAMPLES 2 11 The derivatives of which substituents and melting pointsare collected together in the Table below were prepared according to theprocess described in Example 1 TABLE 1 Instantaneous melting point, A XY R R n Formisolated 0.

-CH2-CHz H H H H 5 Hydrochloride" 210 H H H H 7 ;do 180-185 H H H H142-144. 01-2 H H H 180 01-3 H H H 210 H H H H o 260 H H H H 5 Freeaeid120 H H H 01H5 6 Hydreh10r1de 158-160 H H H H 7 do 150 H H H CzH do128-130 dl7-[8-chloro-dibenzo (b,e) thiepin-ll-yl] aminoheptanoic acidhydrochloride CH2- 1 C1 6 g 5 \A f 8 l 0 \10 a 11 (IJH e1 n-grrcum-coorrTwo g of 4- chloro a nen lraraymini;"gala"was" l g of 8-chloro-dibenzo(b,e) thiepin-l l-one, melting (micro-Kofler) at l52-l53C, was obtained.

4.5 g of 8-chloro-dibenzo (b,e) thiepin-l l-one in ml of methanol weretreated with 1.31 g of sodium bor- TABLE 2 fig ot ill-dichloro-dibenzo(b,e) thiepine were reacted with 9 g of ethyl 7-aminoheptanoate innitromethane in accordance with the process described in Example 1. 10.9g of a product containing 99 percent of ethyl 7-[8-chloro-dibenzo (b,e)thiepin-l l-yl] aminoheptanoate were finally obtained in the form of anon-crystalline gum. 9.9 g of this ester were treated with ml of normalhydrochloric acid and refluxing was continued for 2 hours. The whole wasevaporated in vacuo. The residue was taken up in 50 ml of acetonitrile.The whole was heated under reflux, and then filtered whilst hot. Thefiltered and dried product was then recrystallised from distilled water.6 g of dl 7-[8- chloro-dibenzo (b,e)-thiepin-llyl] aminoheptanoic acidhydrochloride, melting instantaneously at 200210C, were obtained.

EXAMPLES 13 27 The derivatives of which the substituents and meltingpoints are collected together in the Table below were prepared accordingto the process described in Example 12. This Table also contains themelting points of the starting materials used where these are new prod-'ucts;

Melting point Melting point of the of the Instantaneous corresponding;correspondln melting chlorinate ydro xy A X Y R 1R 11 Form isolatedpoint, 0. derivative, 0. derivative, 0.

H H H 0211 5 Hydrochl0r1de 180 Cl-2 H H H 6 d0 204 122-126 138-140 01-3H H v H 190 -84 113-115 F-2 H H H 206 154-158 76-78 H 01-8 H H 6 do 180-115 104-108 01-3 H CH H 5 Free acid -142 0) 01-3 H H H 6 Hydrochloride"210 01-3 01-9 H H 6 do 210 100-102 106-162 C1-2 H H H 5 .d0 200-203104-106 158-160 01-3 H H H 5 d0 181-182 0) 140-142 C1-2 H H H 6 do 01-3H H H 6 do 200 C1-3 H H H 5 do 206 H H H H 5 do 210-212 H H H H de247-248 N01 isolated in the pure state.

EXAMPLE 28 7 d1 6-[ 10-dioxo-l l-methyl dibenzo (c,f) thiazepin (1,2)-5-yll-aminohexanoic acid NIH-(CH1) r-COOH A solution of 8 g (0.05 mol)of freshly distilled ethyl .6-aminocaproate in 10 ml of nitromethanewere added all at once to a well-stirred suspension of 7.3 g (0.025 mol)of 5-chloro-l0-dioxo-l l-methyl-dibenzo (c,f) thiazepine (1,2) in 40 mlof distilled nitromethane. A

slight exothermic reaction was observed with the temperature rising to35C and the halogenated derivative dissolving completely. Stirring wasthen continued for 30 minutes. The reaction mixture was evaporated invacuo. The residue was taken up in 30 ml of water. The insoluble oilwhich separated out was extracted with benzene and the benzene phase waswashed with water and then dried over sodium sulphate. The solvent wasevaporated in vacuo and 10.7 g of crude oily ethyl d1 6-[ l-dioxo-ll-methyl-dibenzo (c,f) thiazepin (1,2)- -yl] aminohexanoate wereobtained, in which the content of pure product determined by measurementwith perchloric scid in an acetic acid medium is 95 percent. 10.4 g ofthis ester thus obtained were treated with 1 g of sodium hydroxidedissolved in 60 ml of ethanol and ml of water. The mixture was keptunder reflux for 45 minutes and then evaporated in vacuo. The residuewas taken up in 30 ml of water andthe aqueous solution was extractedwith ether. The aqueous phase was cautiously acidified to pH 4.5 5. Theacid which precipitated was extracted with chloroform. The chloroformphase was washed and dried, and then evaporated. The 7.3 g of crude acidthus obtained was recrystallised from 10 ml of ethanol and 5.5 g of (116-[10-dioxo-l l-methyl-dibenzo (c,f) thiazepin (1,2)- S-yl]amino-hexanoic acid were thus obtained, melting instantaneously at 118C.

EXAMPLE 29 Ethyl d1 3-[ l0-dioxo-l l-methyl-dibenzo (c,f) thiazepin(1,2)-5-yl] aminopropionate hydrochloride Working as in Example 28 andstarting from 11.6 g of 'S-chloroJO-dioxo-ll-methyl-dibenzo (c,f)thiazepine (1,2) and 9.4 g of ethyl B-aminopropionate, 15 g of dl 3-[l0-dioxo-l l-methyl-dibenzo (c,f) thiazepin (1 ,2)-5-yl]aminopropionatewere obtained, containing 94 percent of pure product as determined bymeasurement with perchloric acid.

Fifteen g of this crude ester were dissolved in 150 ml of anhydrousether and treated with a solution of hydrochloric acid in anhydrousether. The hydrochloride precipitated and was filtered off, washed withether and N dried. 15.5 g of crude ethyl dl 3-[10-dioxo-ll-methyldibenzo (c,f) thiazepin-( l,2)-5-y1] aminopropionatehydrochloride were obtained, which on recrystallisation from wateryielded 12.3 g ofa pure product, melting instantaneously at 210C.

EXAMPLE 30 Sodium 7-[8-chloro-10-dioxo-l l-methyl-dibenzo (c,f)thiazepin-( l ,2)-5-yl aminoheptanoate A solution of 27.6 g (0.16 mol)of freshly distilled ethyl 7-aminoheptanoate in 40 ml of nitromethanewas added all at once and with mechanical stirring to a suspension of26.2 g (0.08 mol) of 5,8-dichloro-l0-dioxollmethyl-dibenzo (c,f)thiazepine (1,2) in ml of nitromethane. The whole was heated to 55C for30 minutes, the solvent was then evaporated in vacuo and the residue wastaken up in water. The crude ester was extracted with ether. Afterevaporation of the ether 36 g of crude ester were obtained, and 30 g(0.065 mol) thereof were treated under reflux with a solution of 2.8 g(0.07 mol) of sodium hydroxide in 75 ml of ethanol and 25 ml of water.After one hour's refluxing, the alcohol was evaporated in vacuo. Theresidue was taken up in ml of water. The mixture was twice extractedwith 75 ml of chloroform and the aqueous phase was evaporated in vacuo.The sodium salt was then dissolved in 150 ml of chloroform, the solutionwas dried over sodium sulphate and the product precipitated withanhydrous ether.

The salt was filtered off, washed with ether and dried at 50C. 13 g ofsodium 7-[8-chloro-l0-dioxo-l lmethyl-dibenzo (c,f) thiazepin(1,2)-5-yl] aminoheptanoate, melting with decomposition at about 180Cwere obtained.

EXAMPLE 31 dl 8-[8-chloro-l0-dioxo-ll-methyl-dibenzo (c,f) thiazepin(1,2)-5-y1] amino-octanoic acid hydrochloride.

(III-I: so,-N CIO/ 01 H-gH- Cihh-COOH 9.35 g (0.050 mol) of freshlyprepared ethyl 8- aminooctanoate were added all at once and whilestirring to a suspension of 8.2 g (0.025 mol) of 5,8 dichloro-lO-dioxo-ll-methyl-dibenzo (c,f) thiazepine (1,2) in 60 ml of nitromethane. Thewhole was kept at 4550C for 20 minutes, the solvent was then evaporatedin vacuo and the crude ester was extracted as in the preceding Examples.

The crude ester was added to 25 ml of 2 N hydrochloric' acid and themixture is boiled for 1 hour, and evaporated to dryness in vacuo. Theresidue was recrystallised from 75 ml of acetonitrile and 7 g of d1 8-[8-chloro-10-dioxo-1l-methyl-dibenzo (c,f) thiazepin (1,2 )--yl]aminooctanoic acid hydrochloride, melting instantaneously at 188 190C,were obtained.

EXAMPLES 32 48 The derivatives of which the substituents and meltingpoints were collected in the Table below were prepared according to theprocess described in Examples 28 to 31. The 5-chloro-10-dioxo-1l-methyl-dibenzo (c,f) thiazepines (1,2) which are the startingmaterials used in Examples 28 to 48 are described in our French PatentNo. 1.566.191

TABLE 3 The stimulant activity on the central nervous system wasdemonstrated by actography in mice. Administered at doeses of 5 tomg/kg, the new compounds increase the number of movings of the animalsfrom four to 10 times compared with the untreated animals 2 hours afterthe administration by subcutaneous, intraperitoneal or oral route. Bythe same test it was observed that the compounds of the inventionantagonize the depressive effects of reserpine at doses of 25 to mg/kg.

The analgesic activity was studied by the method of Woolf G. and MacDonald AD. [.I. Pharm. 80, 300 1944)]. It was found that the compoundsof the invention, administered in mice by intraperitoneal route at dosesof 5 to 20 mg/kg, increase the threshold of pain perception from 30 to170 percent.

The antitussive activity was studied by the method of Gooswald R.[Arzfschg 8, 550 (1958)]. The new compounds, administered bysubcutaneous route in the guinea-pig at doses of 2 to 20 mg/kg, decreasefrom 40 to percent the cough of the animals submitted to a 40 percentcitric acid aerosol for 4 minutes.

The new compounds inhibit the bronchospasm provoiced by intravenousinjection of histamine in the guinea-pig [Konzett and Rossler Arch. Exp.Path. U.

Instantaneous A X Y R R 11 Form isolated Melting df Example: 1

a2 OH; H i H H H 1 Free acid. 220

SO2N

33 Same as above H H H 02115 1 Hydrochloride hemihydrate 180 H CH; Na 3Dih-ydrate 150 H H H 5 Free acid hemihydrate H H H 5 Hydrochloride 21001-8 H H 5 Free acid 50-70 01-8 H H 5 Hydrochloride dihydrate 01-8 H Na5 Sodium salt hemihydrate Cl-7 H Na 5 Sodium salt tctrahydrato.

01-8 H No. 5 Sodium salt 01-8 CH; H 5 Free acid 130 01-8 H Na 10 Sodiumsalt 25 F-8 H H 6 Free acid.

Br-8 C4119 H 6 d0 H H C3H1 3 Hydrochloride 7 CzH5 (31-1 H CH H 5 do so,N

8 Sameasabove 01-4 H H CH 6 do The new tricyclic compounds and theirphysiologically tolerable salts possess valuable pharmacological andtherapeutic properties especially psychostimulant, antidepressive,analgesic, antitussive, antihistaminic and gastric antisecretoryproperties.

Their toxicity is low and the LD, studied in mice varies from 150 to1,000 mg/kg by the intraperitoneal route and from 200 to 1,200 mglkg bythe oral route.

Phar. 195, 71, (1940)]. The spasm is inhibited from 26 to 75 percent byintravenous doses of 2,5 to 5 mg/kg.

The gastric antisecretory activity was studied by the method of H. Shayet al. [Gastroenterology 5, 43 (1945)]. It was observed that the newcompounds inhibit the gastric secretion in rat at doses of 5 to 50 mg/kgby intraperitoneal route. The decrease of the volume of gastricsecretion in treated animals varies from 20 to 70 percent compared withthe untreated animals 4 hours after the ligature of pylorus.

The hereabove described properties, as well as the low toxicity, allowthe use of the new compounds in therapy, especially in the treatment ofpsychoneurotic disorders, pain, cough and gastric hypersecretion.

The present invention also includes pharmaceutical compositions fororal, rectal or parenteral administration, containing a compound of thegeneral formula I or a physiologically tolerable salt thereof, inadmixture or conjunction with a suitable pharmaceutical carrier, such,for example, as distilled water, glucose, lactose, talc, starch,magnesium stearate and cocoa butter.

Doses may vary from 10 to 100 mg one to five times a day.

We claim l. A compound selected from the group consisting of A.tricyclic compounds of the general formula wherein A is a bridgeselected from the following radicals (CH and CH CH, in which m is aninteger of from 1 to 3 inclusive X and Y are selected from the groupconsisting of hydrogen and halogen selected from fluorine, chlorine andbromine R and R are selected from the group consisting of hydrogen andlower alkyl having from one to five carbon atoms inclusive and n is aninteger of from 1 to 12 inclusive and,

B. physiologically tolerable addition salts with suitable bases or acidswhen R is hydrogen, and with suitable acids when R is lower alkyl havingfrom one to five carbon atoms inclusive.

2. A compound of claim 1 which is 7-[dibenzo (a,d)

cycloheptadien-S-yl] aminoheptanoic acid.

3. A compound of claim 1 which is 7-[dibenzo (a,d)

cyclooctadien-S-yl] aminoheptanoic acid.

4. A compound of claim 1 which is ethyl ll-[dibenzo (a,d)cycloheptatrien-5-yl] aminoundecanoate.

5. A compound of claim 1 which is 7-[2-chloro dibenzo (a,d)cycloheptadien-S yl] amino heptanoic acid.

2. A compound of claim 1 which is 7-(dibenzo (a,d) cycloheptadien-5-yl) aminoheptanoic acid.
 3. A compound of claim 1 which is 7-(dibenzo (a,d) cyclooctadien-5-yl) aminoheptanoic acid.
 4. A compound of claim 1 which is ethyl 11-(dibenzo (a,d) cyclo-heptatrien-5-yl) aminoundecanoate.
 5. A compound of claim 1 which is 7-(2-chloro dibenzo (a,d) cycloheptadien-5 yl) amino heptanoic acid. 